EP2296772B1 - Protéines amphiphiles en tant que modificateurs de la morphologie - Google Patents

Protéines amphiphiles en tant que modificateurs de la morphologie Download PDF

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Publication number
EP2296772B1
EP2296772B1 EP09793912.8A EP09793912A EP2296772B1 EP 2296772 B1 EP2296772 B1 EP 2296772B1 EP 09793912 A EP09793912 A EP 09793912A EP 2296772 B1 EP2296772 B1 EP 2296772B1
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Prior art keywords
solution
protein
organic substance
dispersion
hydrophobin
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Not-in-force
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EP09793912.8A
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German (de)
English (en)
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EP2296772A1 (fr
Inventor
Andreas Hafner
Andreas Buthe
Paul Adriaan Van Der Schaaf
Franz Kaufmann
Gordon Bradley
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BRAIN Biotech AG
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BRAIN Biotechnology Research and Information Network AG
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/37—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from fungi
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the present invention relates to a process for modifying the morphology and/or polymorphism of solid organic compounds as characterized in the appended claims.
  • Solidification and especially crystallization is a key separation and purification unit in most of the pharmaceutical, food and specialty chemical processes (for example pigments), with a significant impact on the efficiency and profitability of the overall process.
  • the majority of pharmaceutical products contain active ingredients produced in crystalline form.
  • crystallisation is of fundamental importance to the industry.
  • product effectiveness e.g. bioavailability, tablet stability
  • Figure 9 illustrates a typical crystallization process embracing the following steps:
  • Supersaturation is the driving force of the crystallization, hence the rate of nucleation and growth is driven by the existing supersaturation in the solution.
  • Supersaturation is defined as concentration of the solute in excess of saturated concentration under given conditions of temperature. Once supersaturation is lost, the solid-liquid system reaches equilibrium and the crystallization process stops.
  • Certain solvents, the presence of impurities or additives and compounds of similar chemical type to the compound undergoing the crystallization process can strongly influence its nucleation and crystal growth stages by changing the supersaturation properties of the crystallization process.
  • nucleation or growth may be predominant over the other, and as a result, crystals with different sizes, different size distributions and habits (shapes) are obtained.
  • Crystal habits can be, for example, cubic, tetragonal, orthorhombic, hexagonal, monoclinic, triclinic, and trigonal.
  • Different polymorphs can also be produced by changes in the crystallization process.
  • Polymorphs are defined as crystalline phases that have different arrangements and/or conformations of molecules in the crystal lattice. These crystal forms differ in packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties.
  • polymorphs have the same elemental composition, polymorphs exhibit different physico-chemical and physicotechnical properties such as free energy, entropy, heat capacity, melting point, sublimation temperature, solubility, stability, dissolution rate, bioavailability, hardness, compatibility, flowability, tensile strength and compressibility, etc.
  • Synthetic (co)polymers and surfactants have also been shown to modify the morphology of bio-active substances but this has limited commercial value again on toxicity grounds.
  • WO03/033462 proposes polymer libraries for initiating growth of crystal polymorphs and describes the use of certain polymers to modify the crystallization of paracetamol: The crystals are grown by cooling a solution of paracetamol in hot water. In the absence of polymers, these conditions would be expected to yield monoclinic paracetamol. There is a significant bias toward the production of orthorhombic paracetamol when crystallizations are carried out in the presence of Nylons or halogenated polymers.
  • Rodr ⁇ guez-Hornedo et al., J Pharm Sci. (2004) 93(2), 449-60 describe the use of surfactants sodium lauryl sulfate and sodium taurocholate on the crystallization of dihydrate carbamazepine.
  • WO 05/115344 claims that a rapidly dissolving form of paracetamol is obtained after recrystallization in the presence of a crystallization modifier, which may be a polymer, or a protein such as albumin, papain, pepsin.
  • a crystallization modifier which may be a polymer, or a protein such as albumin, papain, pepsin.
  • Hydrophobins may be used as additives during or after crystallization, e.g. in order to control the morphology (stabilization of metastable polymorphs) and the size distribution of organic compounds such as bio-active substances, e.g. for cosmetical, biocidal, pharmaceutical or medical applications (such as cosmetical actives, active pharmaceutical ingredients [APIs], animal care products, agrochemicals, biocides, pigments, dyestuffs) or to stabilize certain polymorphs.
  • bio-active substances e.g. for cosmetical, biocidal, pharmaceutical or medical applications (such as cosmetical actives, active pharmaceutical ingredients [APIs], animal care products, agrochemicals, biocides, pigments, dyestuffs) or to stabilize certain polymorphs.
  • the invention thus pertains to a process for modifying the morphology and/or polymorphism of an organic substance, which process comprises treating the solid substance, or a solution or dispersion thereof, with one or more amphiphilic proteins, as characterized in the appended claims.
  • the process is advantageously carried out using a solution or dispersion of the organic substance and/or solution or dispersion of the protein.
  • the solution usually is one in a polar solvent, often an aqueous solvent such as water, lower alcohol (such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol) or mixtures of water and lower alcohol, especially water.
  • One of the most important aspects of this invention is the modification of crystal properties of bio-active substances by employing the use hydrophobins during the crystallization process.
  • bio-active substances are found to be poorly soluble in water, and it is known that forming finer particles (micron and smaller) can improve their bio-availability or the dissolution rate due to their increased surface area.
  • compositions comprising an organic bio-active substance and an amphiphilic protein, especially a hydrophobin, such as the compositions obtainable in the process of the invention.
  • the composition contains the organic bio-active substance preferably in fine grain form, with mean particle sizes, depending on the desired end use, e.g. ranging from 0.1 to 1000 micrometer, or in other cases as detectable by dynamic light scattering ranging e.g. from 5 to 5000 nm, especially 20 to 2000 nm. Such particles may be free flowing, dispersed in a liquid, or especially agglomerated or compacted.
  • the amount of amphiphilic protein in the composition e.g.
  • the solid particle composition may cover a wide range depending un the end use and desired effect, ranging for example from about 0.0001 to about 10 %, often from 0.001 to about 2 %, especially 0.01 to about 1 %, each by weight of the final composition.
  • the present process relates to a modification which comprises a reduction of the crystallite size.
  • Also described herein is a process relating to a modification which comprises a change of crystal habit.
  • Amphiphatic proteins can physically adsorb on the surface of a solid substance to form a surface possessing both hydrophobicity and hydrophilicity oriented in accordance with the wettability of the surface being treated.
  • the hydrophobic side of the coating is in contact with the hydrophobic surface being coated, and the outer surface of the coating is hydrophilic, thereby increasing the water wettability of the surface being coated.
  • the surface active properties of proteins onto substrates can be assessed by interfacial tension measurements, characterization of oil-in-water emulsions and contact angles with water.
  • the amphiphilic protein useful in the present invention is characterized by strongly lowering the contact angle of water (WCA) on a hydrophobic surface (e.g. the surface of a polyolefin or a Teflon® surface). Specifically, a 1% b.w.
  • Hydrophobins discovered in 1991, are a class of small secreted cysteine-rich amphiphilic proteins present in fungi and fulfilling a broad spectrum of functions in fungal growth and development. Hydrophobins are among the most surface active molecules and self-assemble at any hydrophilic-hydrophobic interface into an amphiphilic film ( Biochimica et Biophysica Acta - Reviews on Biomembranes - Volume 1469, Issue 2, 18 September 2000, Pages 79-86 ).
  • Hydrophobins are typically readily soluble in water. Spontaneous self-assembly of hydrophobins leads to the formation of an amphiphilic layer that remarkably reduces the surface tension of water.
  • a suggested mechanism of the function for hydrophobins can be found in J. Biol. Chem., Vol. 282, Issue 39, 28733-28739, September 28, 2007 : Monomers multimerize to dimers, two of which form a tetramer. The tetramer may split into two new dimers with hydrophobic surface areas aligned. These amphiphilic dimers precede the formation of amphiphilic monolayer on hydrophobic-hydrophilic interface. At high concentration, excess hydrophobin forms fibril structures.
  • hydrophobins are divided into two categories: class I and class II.
  • hydrophobins useful in the present invention are described inter alia in WO 96/41882 (see passage from page 1, line 14, to page 7, line 20, and examples 1 to 5); WO 03/10331 (see passage from page 1, line 4, to page 5, line 20); or WO 06/103230 (see passage from page 3, paragraph 6, to page 12, 3 rd line from bottom of page).
  • hydrophobins also affect the morphological properties of organic substances and often give more advantageous compositions than when solvents, polymers or synthetic surfactants are used.
  • the present process often is carried out by
  • an amphiphilic protein especially as characterized by lowering of the contact angle as described above, especially a hydrophobin as described above, for modifying the morphology and/or polymorphism of an organic substance; as well as a composition comprising a solid organic substance, especially an organic compound, which is solid at 0° Celsius and soluble, partially soluble or dispersable in the polar solvent, for example as a colloid, and/or an organic compound from the molecular weight range 80 to 1000, especially 100 to 500 g/mol, which is preferably selected from bio-active compounds such as drugs, pharmaceutical and cosmetical ingredients, pesticides, and fungicides, in combination with the amphiphilic protein.
  • Said composition preferably comprises the solid organic substance in the form of fine grain particles.
  • acepromazine amoxicillin, ampicillin, apramycin, benazepril, betamethasone, buscopan, carprofen, cefapirin, clenbuterol, clindamycin, cloxacillin, cyclosporine A, cyromazine, deracoxib, dichlorvos, dicyclanil, difloxacin, enrofloxacin, etodolac, fenbendazole, framycetin, furosemide, griseofulvin, hetacillin, hygromycin, imidacloprid, levamisole, levothyroxine, lufenuron, meloxicam, milbemycin oxime, monensin, moxidectin, narasin, nicarbazin, nitenpyram, oleandomycin, oxfendazole, oxyclozanide, paramectin, par
  • Agrochemicals such as pesticides and fungicides: abamectin, brodifacoum, cyromazine, emamectin, fenoxycarb, pirimicarb, pymetrozine, thiamethoxam.
  • UV filter substances e.g. (+/-)-1,7,7-trimethyl-3-[(4-methylphenyl)methylene]bicyclo-[2.2.1]heptan-2-one; 1,7,7-trimethyl-3-(phenylmethylene)bicyclo[2.2.1]heptan-2-one; (2-Hydroxy-4-methoxyphenyl)(4-methylphenyl)methanone; 2,4-dihydroxybenzophenone; 2,2',4,4'-tetrahydroxybenzophenone; 2-Hydroxy-4-methoxy benzophenone; 2-Hydroxy-4-methoxy benzophenone-5-sulfonic acid; 2,2'-dihydroxy-4,4'-dimethoxybenzophenone; 2,2'-Dihydroxy-4-methoxybenzophenone; Alpha-(2-oxoborn-3-ylidene)toluene-4-sulphonic acid and its salts; 1-[4-(1,1-dimethyl
  • active ingredients having a keratoplastic effect e.g. benzoyl peroxide, retinoic acid, colloidal sulfur and resorcinol
  • antimicrobial agents for example triclosan or quaternary ammonium compounds
  • Organic pigments such as phthalocyanines, azos, etc
  • Organic dyes such as solvent dyes, direct dyes etc
  • the invention is not limited to the above list of organic substances.
  • Room temperature depicts a temperature in the range 20-25°C; over night denotes a time period in the range 12-16 hours. Percentages are by weight, temperatures by degrees Celsius (centigrade) unless otherwise indicated.
  • Hydrophobin solution Aqueous solutions are used containing 10 mg protein/ml solution. Hydrophobins are produced recombinantly in E. coli ; these are
  • the hydrophobin solution is prepared by solubilization of 10 mg of lyophilized powder (protein content at least 60-80%) in 1 mL pure water. Insoluble residues are removed by centrifugation.
  • Control samples are treated in the same way except that 100 ⁇ L of pure water are added instead of the hydrophobin solution, or no API is present. Crystallization behaviour is assessed visually; the results are compiled in the following table.
  • Table 1 Sample protein API after 0 min ⁇ 5 min 15 min > 20 h control none yes streaks clear clear crystals 1-2 mm invention SC yes streaks clear cryst. 0.1-0.2 mm crystals 0.5 mm control SC - clear invention TR yes streaks clear clear crystals 0.5 mm control TR - clear invention PO yes clouding few crystals 0.2-0.5 mm cryst. 0.2-0.5 mm crystals 0.5-1 mm control PO - clear invention TT yes clouding few cryst. 0.1 mm crystals 0.1 mm crystals 0.5-1 mm control TT - clear
  • Example 2 Crystallisation of benzamide in presence of SC, PO, TT or TR
  • Control samples are treated in the same way except that 100 ⁇ L of pure water are added instead of the hydrophobin solution, or no API is present.
  • the results of a visual assessment after the hydrophobin injection (final concentration in the sample is 100 ppm) are compiled in the following table.
  • Clouding is interpreted as the formation of small API crystals. At room temperature, crystallization is far advanced and the tube is filled with a bulky mass of crystal aggregates which does not allow determination of crystal size.
  • the mother liquor crystallizes completely over night, with crystals adhering together covered by the solvent. Vigorous shaking (Vortex) for 10-15 sec is accompanied by different degrees of re-suspension: pouring the suspensions into dishes results in complete emptying of the tubes for the samples containing SC and TR, while for samples containing PO, TT, and the control sample, predominantly the remaining mother liquor is poured out. Best dispersability is obtained in presence of SC or TR .
  • Example 5 Crystallisation of paracetamol or benzamide, varying protein concentration
  • All solutions and aliquots are prepared as described in example 1 and 2 except that 500 ⁇ L of a solution with different amounts of TR (to adjust final concentrations of 100 / 250 / 500 / 750 /1000 ppm) are added.
  • the TR stock solution is prepared by solubilizing 30 mg lyophilized TR in 1.5 mL pure water. The injection of the TR solution is not accompanied by turbidity, but for concentrations over 250 ppm the liquid starts getting slightly clouded after less than 5 min. At that time, 5 mL of each sample is poured into a dish to allow crystallization by evaporation.
  • crystal size fractions are determined by the single-particle optical sensing (SPOS) method ( AccuSizer 780 / A, Particle Sizing Systems ). Without hydrophobin, the crystal size predominantly ranges from 0.1 to 2 mm; the addition of TR leads to the formation of a class of smaller particles in the size range of 5-50 ⁇ m. Further, the presence of TR significantly reduces the size of the most abundant particles of the "large” fraction (see fig. 7 ). The hydrophobin-induced shift between the two predominant size fractions is compiled in table 5.
  • SPOS single-particle optical sensing

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Claims (7)

  1. Procédé pour modifier la morphologie et/ou le polymorphisme d'une substance organique, lequel procédé a pour but la réduction de la taille des cristallites, lequel procédé comprend le traitement de la substance solide, ou d'une solution ou dispersion de celle-ci, avec une ou plusieurs protéines amphiphiles, laquelle protéine amphiphile est une hydrophobine, telle qu'une hydrophobine de classe II ou en particulier une hydrophobine de classe I, et lequel procédé comprend
    i) la combinaison de la solution ou dispersion de la protéine dans un solvant polaire, et d'une solution ou dispersion de la substance organique dans un solvant polaire qui est miscible avec le solvant de la protéine, ou
    ii) la mise en contact de la solution ou dispersion de la substance organique dans un solvant polaire avec une surface imprégnée de la protéine.
  2. Procédé selon la revendication 1, qui comprend le broyage à l'état humide de la substance organique en présence de la ou des protéines amphiphiles.
  3. Procédé selon l'une quelconque des revendications précédentes, qui comprend l'addition de germes cristallins de la substance organique à la solution de la substance organique, avant ou après l'addition de la ou des protéines amphiphiles.
  4. Procédé selon l'une quelconque des revendications précédentes, dans lequel la solution contient un autre additif tel qu'un sel et/ou un polymère.
  5. Procédé selon l'une quelconque des revendications précédentes, dans lequel la substance organique est un composé organique qui est solide à 0 °C et soluble, partiellement soluble ou dispersible dans le solvant polaire, par exemple sous la forme d'un colloïde.
  6. Procédé selon l'une quelconque des revendications précédentes, dans lequel la substance organique est un composé organique ayant une masse moléculaire située dans la plage allant de 80 à 1000, en particulier de 100 à 500 g/mol, qui est de préférence choisi parmi les composés bioactifs tels que les médicaments, les ingrédients pharmaceutiques et cosmétiques, les pesticides, et les fongicides.
  7. Procédé selon l'une quelconque des revendications précédentes, dans lequel la précipitation ou la cristallisation de la substance organique est induite par combinaison d'une solution ou dispersion de celle-ci avec la solution ou dispersion de la protéine amphiphile.
EP09793912.8A 2008-07-11 2009-06-23 Protéines amphiphiles en tant que modificateurs de la morphologie Not-in-force EP2296772B1 (fr)

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EP09793912.8A EP2296772B1 (fr) 2008-07-11 2009-06-23 Protéines amphiphiles en tant que modificateurs de la morphologie

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EP08160212 2008-07-11
EP09793912.8A EP2296772B1 (fr) 2008-07-11 2009-06-23 Protéines amphiphiles en tant que modificateurs de la morphologie
PCT/EP2009/057760 WO2010003811A1 (fr) 2008-07-11 2009-06-23 Protéines amphiphiles utilisables en vue d'une modification morphologique

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EP2296772B1 true EP2296772B1 (fr) 2017-08-02

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US (1) US20110159050A1 (fr)
EP (1) EP2296772B1 (fr)
JP (1) JP2011527668A (fr)
KR (1) KR20110043655A (fr)
CN (1) CN102089051A (fr)
WO (1) WO2010003811A1 (fr)

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US8507726B2 (en) * 2008-11-03 2013-08-13 Basf Se Photoinitiator mixtures
CA2750421C (fr) 2008-11-27 2016-10-18 B.R.A.I.N. Biotechnology Research And Information Network Ag Proteines tensioactives en tant qu'excipients dans des formulations pharmaceutiques solides
WO2010097344A1 (fr) 2009-02-26 2010-09-02 Basf Se Compositions, utilisation et procédé d'utilisation de protéines tensioactives dans la délivrance topique de médicaments à travers la kératine
FI20095638A0 (fi) * 2009-06-09 2009-06-09 Valtion Teknillinen Hydrofobiineja aktiivisten aineiden dispergointiin
SI3017811T1 (sl) 2010-02-25 2019-04-30 Bristol-Myers Squibb Holdings Ireland Unlimited Company Formulacije apiksabana
WO2012013508A1 (fr) 2010-07-30 2012-02-02 Basf Se Protéine amphiphile utilisée en électronique imprimée
EP3214932A1 (fr) * 2014-11-05 2017-09-13 Basf Se Procédé de préparation d'une composition agrochimique de toxicité réduite par broyage d'un pré-mélange de pesticide et d'une hydrophobine

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US20110159050A1 (en) 2011-06-30
CN102089051A (zh) 2011-06-08
EP2296772A1 (fr) 2011-03-23
JP2011527668A (ja) 2011-11-04
WO2010003811A1 (fr) 2010-01-14
KR20110043655A (ko) 2011-04-27

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